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Jean-Pierre Raufman, MD

The Moses Paulson, MD and Helen Golden Paulson Chair in the Division of Gastroenterology

Academic Title:

Professor

Primary Appointment:

Medicine

Administrative Title:

Division Head, Gastroenterology & Hepatology

Location:

22 S. Greene Street, Room N3W62

Phone (Primary):

410-328-8728

Fax:

410-328-8315

Education and Training

Dr. Raufman is board certified in Internal Medicine and Gastroenterology. He is a graduate of Albert Einstein College of Medicine, and trained at the University of Michigan and the National Institutes of Health. He has published more than 150 original papers and more than 25 book chapters. He is a member of the American Society for Clinical Investigation and has served on several NIH Study Sections and an FDA Advisory Panel. Dr. Raufman is the Program Director for an NIDDK T32 Training Grant, Training in Gastroenterology Research.

Dr. Raufman is a member of the Molecular and Structural Biology Program within the University of Maryland Marlene and Stewart Greenebaum Cancer Center Program in Oncology. As such, he collaborates with both basic and clinical research investigators to identify candidate proteins and genes that are relevant to muscarinic receptor signaling in colon cancer and may serve as markers for malignancy and/or targets for new drugs.

Biosketch

I completed GI Fellowship training at the University of Michigan where I worked in the lab of Dr. Jorge Gumucio (1978-80). I obtained three more years of research training at the National Institutes of Health in the NIDDK, Digestive Diseases Branch under the mentorship of Drs. Jerry D. Gardner and Robert T. Jensen (1980-83). Since July 1983, I maintain an independent research program whose unifying theme is the study of gastrointestinal regulatory molecules and signal transduction; I have been funded by R01, R21 and T32 awards from NIH (NIDDK and NCI), by the VA Merit program, and by foundations (e.g. AGA/Industry Award). I presented my work at prominent national meetings, secured patents, and published more than 180 peer-reviewed research papers, reviews and book chapters (including 19 first- or senior-author scientific publications in the American Journal of Physiology, nine in the Journal of Biological Chemistry, three each in Biochemical Pharmacology and Biomedical Biophysical Research Communications, two each in Cancer Research, Journal of Pharmacology and Experimental Therapeutics, Carcinogenesis, Molecular Cancer, and PLoS One, and one each in Proceedings of the National Academy of Sciences (USA), Experimental Cell Research, and the Biochemical Journal).

Highlighted Publications

  1. Raufman J-P, Dawson PA, Rao A, Drachenberg CB, Heath J, Shang AC, Hu S, Zhan M, Polli JE, Cheng K. Slc10a2-null mice uncover colon cancer-promoting actions of endogenous fecal bile acids. Carcinogenesis 36:1193-1200, 2015. doi: 10.1093/carcin/bgv107

  2. Rachakonda V, Jadeja R, Urrunaga N, Shah N, Ahmad D, Cheng K, Twaddell W, Raufman, J-P, Khurana S. M1 muscarinic receptor deficiency attenuates azoxymethane-induced chronic liver injury in mice. Scientific Reports 5:14110, 2015. doi:10.1038/srep14110

  3. Hu S, Liu L, Chang EB, Wang J-Y, Raufman J-P. Butyrate inhibits pro-proliferative miR-92a by diminishing c-Myc-induced miR-17-92a cluster transcription in human colon cancer cells. Molecular Cancer 14:180, 2015. doi: 10.1186/s12943-015-0450-x

  4. McLean L, Smith A, Cheung L, Urban J, Sun R, Grinchuk V, Desai N, Zhao A, Raufman J-P, Shea-Donohue T. Type 3 muscarinic receptors contribute to intestinal mucosal homeostasis and clearance of Nippostrongylus brasiliensis through Induction of Th2 cytokines. Amer. J. Physiol. (Gastrointest. Liver Physiol.) 311:G130-141, 2016.  doi:10.1152/ajpgi.00461.2014.

  5. Felton J, Cheng K, Said A, Shang AC, Xu S, Vivian D, Metry M, Polli J, Raufman J-P. Using multi-fluorinated bile acids and in vivo magnetic resonance imaging to measure bile acid transport. Journal of Visualized Experiments (JoVE) 2016. (In press)

Research Interests

Over the past decade, our laboratory has explored the implications of my discovery that bile acids interact functionally with muscarinic receptors. Whereas it was observed for decades that changes in fecal bile acid composition increase the risk of colon cancer in both animal models and humans, the underlying mechanisms were elusive. Colon cancer cells over-express muscarinic receptor subtype 3 (M3R; gene name CHRM3). We found that bile acids and conventional muscarinic agonists (e.g. acetylcholine) stimulate colon cancer cell proliferation and survival by activating M3R, trans-activating EGFR and stimulating post-receptor signaling, primarily via ERK and PI3K activation. In vivo work using two mouse models of colon cancer revealed that activation of muscarinic receptors increases the number of colon adenocarcinomas, whereas reduced expression or activation of M3R attenuates colon neoplasia.

The work in our lab currently focuses on: (a) Elucidating the functional interaction between M3R and MMP1, a collagenase whose expression in colon cancer cells is robustly increased by M3R activation. With VA Merit funding, we are exploring the mechanisms whereby M3R agonists promote MMP1 gene induction by newly-identified cross-talk between EGFR/ERK and PKC/p38, and will test the hypothesis that MMP1 can be targeted successfully to attenuate colon cancer cell invasion and dissemination. (b) Elucidating the role of a Cdc42/Rac nucleotide exchange factor, βPix, as a pivotal molecule mediating interaction between muscarinic receptor and β-catenin signaling in colon cancer. To accomplish this goal we created mice with conditional intestine-selective βPix deletion.

Our long-term goal is to apply resulting advances in knowledge to prevent and treat colon cancer. Publications of particular importance with regard to our work in colon cancer include:

  1. Cheng, K, Zimniak, P, Raufman, J-P. Transactivation of the epidermal growth factor receptor mediates cholinergic agonist-induced proliferation of H508 colon cancer cells.  Cancer Res. 63:6744-50, 2003.

  2. Raufman, J-P., Samimi, R., Shah, N., Khurana, S., Shant, J.,  Drachenberg, C., Xie, G., Wess, J., Cheng, K. Genetic ablation of M3 muscarinic receptors attenuates murine colon epithelial cell proliferation and neoplasia. Cancer Res. (Priority Report) 68:3573-78, 2008. (PMCID 2577901)

  3. Chahdi A, Raufman J-P. The Cdc42/Rac nucleotide exchange factor β1Pix modulates β-catenin transcriptional activity in colon cancer cells. J. Biol. Chem. 288:34019-34029, 2013. (PMCID 3837141)

  4. Hu S, Liu L, Chang EB, Wang J-Y, Raufman J-P. Butyrate inhibits pro-proliferative miR-92a by diminishing c-Myc-induced miR-17-92a cluster transcription in human colon cancer cells. Molecular Cancer 14:180, 2015. doi: 10.1186/s12943-015-0450-x

Grants and Contracts

VA Merit Award BX002129                           PI: Raufman, J-P                                                                                                                        10/01/14-09/30/18

Department of Veterans Affairs                    M3R, MMP1 and Colon Cancer Dissemination

The goals are to determine the mechanisms whereby M3R agonist-induced MMP1 expression stimulates human colon cancer cell invasion and dissemination.

Role: PI

 

T32 DK067872               

PI: J-PRaufman                                                                                                                                        07/01/05-6/30/20

NIH/NIDDK                                                                          Research Training in Gastroenterology

Role: PD; Director, Cell Signaling and Proliferation track

 

NIH Contract NO2-DK-5-2802                      Raufman (PI)                                                                                                                                     07/01/05-06/30/16

NIH/NIDDK                                                                             Gastroenterology Fellowship and Consultations at NIH

Role: PI

 

VA Merit Award                                                                      Wang, J-Y (PI)                                                                                                                        04/01/14-03/31/18

Department of Veterans Affairs                    Regulation of intestinal epithelial restituition

The goals are to determine the roles and mechanisms of RNA-binding protein HuR and microRNAs in the regulation of GI mucosal restitution after mucosal injury.

Role: Co-Investigator

 

F31 DK105750-01A1                                                 Garzel, B (PI)                                                                                                                         07/01/15-06/30/17

NIDDK                                                                                               Role of BSEP in drug-induced cholestatic liver toxicity

Role: Co-Mentor

 

R01 DK068491                                                                      Wang, J-Y (PI)                                                                                                                                   10/01/15-10/30/20

NIDDK                                                                                               Surgical studies of gut permeability

Role: Co-Investigator

 

T32 DK098107                                                                      Taylor, S (PI)                                                                                                                        07/01/15-06/30/18

NIDDK                                                                                               Diabetes and its metabolic complications

Role: Internal Advisory Committee